JAIDS Journal of Acquired Immune Deficiency Syndromes:
Distinct Patterns of Emergence and Fading of K103N and Y181C in Women With Subtype A vs. D After Single-Dose Nevirapine: HIVNET 012
Eshleman, Susan H MD, PhD*; Guay, Laura A MD*; Wang, Jing MS†; Mwatha, Anthony MS†; Brown, Elizabeth R PhD†‡; Musoke, Philippa MBChB§; Mmiro, Francis MBChB§; Jackson, J Brooks MD, MBA*
From *The Johns Hopkins Medical Institutions, Baltimore, MD; †Fred Hutchinson Cancer Research Center, Seattle, WA; ‡University of Washington, Seattle, WA; and §Makerere University, Kampala, Uganda.
Received for publication January 13, 2004; accepted June 10, 2005.
Supported by (1) the HIV Network for Prevention Trials (HIVNET) and sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Dept. of Health and Human Services (DHHS), through contracts with Family Health International (N01-AI-35173 and Fred Hutchinson Cancer Research Center (N01-AI-45200) and a subcontract with Makerere University (NOI-AI-35173-417); (2) the HIV Prevention Trials Network (HPTN) sponsored by the NIAID, National Institutes of Child Health and Human Development (NICH/HD), National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the NIH, DHHS (U01-AI-46745 and U01-AI-48054); (3) the Adult AIDS Clinical Trials Groups (NIH, Division of AIDS, NIAID, U01-AI-38858); and (4) R01-HD042965-01.
Reprints: Susan Eshleman, Department of Pathology, The Johns Hopkins Medical Institutions, Ross Bldg. 646, 720 Rutland Ave., Baltimore, MD 21205 (e-mail: firstname.lastname@example.org).
Background: The HIVNET 012 trial in Uganda demonstrated that single-dose nevirapine (NVP) can prevent HIV-1 mother-to-child transmission. NVP resistance (NVPR) mutations were detected in 25% of women 6 to 8 weeks after NVP, with a higher rate of NVPR in women with subtype D than A. This study examined emergence and fading of specific NVPR mutations in women with these subtypes.
Methods: Plasma HIV-1 was analyzed with the ViroSeq genotyping system (Celera Diagnostics, Alameda, CA). Genotypes were obtained from paired samples collected 7 days and 6 to 8 weeks after NVP from 140 women, 83 with subtype A and 57 with subtype D.
Results: The rate of NVPR was similar in women with subtype A vs. D at 7 days but was higher in subtype D than A at 6 to 8 weeks. The higher rate of NVPR in subtype D was explained by at least 2 factors: Y181C faded from detection at a greater rate in women with subtype A (odds ratio = 3.06; 95% CI, 1.04, 8.90) and K103N accumulated at a greater rate in women with subtype D (odds ratio = 1.74; 95% CI, 0.62, 4.87).
Conclusions: HIV-1 subtype influences selection and fading of HIV-1 variants with specific drug resistance mutations after antiretroviral drug exposure.
Use of antiretroviral drugs for HIV-1 treatment and prevention is often associated with selection of strains with mutations in HIV-1 protease and reverse transcriptase (RT). Most information about HIV-1 drug resistance comes from analysis of subtype B HIV-1. However, most HIV-1 infections worldwide are caused by other HIV-1 strains. Understanding the relationship between HIV-1 subtype and antiretroviral drug resistance is becoming increasingly important as the availability of antiretroviral drugs increases in countries where non-subtype B strains are prevalent. Most studies of HIV-1 drug resistance have focused on individuals receiving prolonged courses of antiretroviral drugs for HIV-1 treatment. Further studies are also needed to evaluate drug resistance in resource-limited settings where individuals receive only a brief exposure to antiretroviral drugs for prevention of HIV-1 transmission.
Some studies suggest that subtype may influence the susceptibility of HIV-1 to certain antiretroviral drugs.1,2 Polymorphisms at amino acid positions associated with drug resistance are often detected in antiretroviral-naive individuals with non-subtype B infection.3,4 Such subtype-based differences may influence the rate at which specific mutations emerge5 and the types of mutations selected under drug pressure.6,7 Sequence differences among HIV strains may also lead to emergence of novel subtype-specific resistance mutations.8 Few studies have examined whether subtype influences virologic response to antiretroviral therapy. Those that have are generally rather small and patients were treated with varying regimens and for varying lengths of time.9,10
The HIVNET 012 trial in Uganda demonstrated that a single-dose regimen of nevirapine (NVP) prophylaxis was safe and effective for prevention of HIV-1 mother-to-child transmission (pMTCT).11,12 Most of the women enrolled in HIVNET 012 had either subtype A or D infection, and all were antiretroviral drug naive prior to NVP administration. Women received a single 200-mg NVP dose at the onset of labor, and infants received a single 2-mg/kg NVP dose shortly after birth. Women did not receive any other antiretroviral therapy, consistent with the standard of care in Uganda at the time the trial was performed. Subsequent trials have confirmed that 1- or 2-dose NVP regimens are safe and effective for pMTCT.13-15 The HIVNET 012 regimen is endorsed by the World Health Organization for use in resource-limited settings.16
A potential disadvantage of the HIVNET 012 regimen is the emergence of NVP resistance (NVPR) in women and infants after NVP administration. In HIVNET 012, NVP-resistant HIV-1 strains were detected in 70 (25%) of 279 women17 and 11 (46%) of 24 infants18 6 to 8 weeks after delivery. NVPR was also detected in some women as early as 7 days after single-dose NVP.19 Emergence of NVPR in this setting is favored by 2 factors. First, single mutations in HIV-1 RT (eg, K103N, Y181C) can cause high-level NVP resistance, and HIV-1 variants with those mutations are thought to exist at low levels in most HIV-1-infected individuals, including those who are antiretroviral drug naive.20 Second, the half-life of NVP in pregnant women is long.21,22 Low levels of NVP may be detectable for >3 weeks after a single NVP dose,23 providing time for selection of resistant variants.
Studies suggest that the frequency of NVPR in women after single-dose NVP may be influenced by HIV-1 subtype. In HIVNET 012, the rate of NVPR was significantly higher in women with subtype D than A at 6 to 8 weeks postpartum (35.7% vs. 19%, respectively, P < 0.01).17,24 This did not appear to reflect more advanced disease among women with subtype D, because the baseline viral loads and baseline CD4 cell counts were similar for women with these 2 subtypes.17 NVPR was detected in 74 of 111 (67%) of South African women with subtype C 4 to 6 weeks after they received a 2-dose regimen of NVP for pMTCT25 and in 45 of 65 (69%) of Malawian women with subtype C 6 to 8 weeks after single-dose NVP.26,27 The rate of NVPR in the Malawian women was significantly higher than the rate observed in Ugandan women in HIVNET 012 with subtype A or D, even after adjusting for age, parity, baseline viral load, and the time between NVP dosing and resistance testing.27
In HIVNET 012, we observed a shift in the predominant NVPR mutation from Y181C at 7 days to K103N at 6 to 8 weeks after single-dose NVP.19 However, the subset of women included in that study was too small to compare the selection and fading of specific NVPR mutations in subtype A vs. D. Since that study was completed, additional samples were provided by the HIVNET 012 team for resistance studies. The availability of additional samples allowed us to extend the previous study to examine the impact of HIV-1 subtype on the emergence and fading of specific NVPR mutations following single-dose NVP exposure.
MATERIALS AND METHODS
Research in this study was performed according to federal and institutional policies.
Samples Used for Analysis
Genotypes were obtained from plasma samples collected from women in the HIVNET 012 trial either 7 days or 6 to 8 weeks after NVP administration. Baseline (pre-NVP) viral load and baseline CD4 cell count were determined for women in the HIVNET 012 study.11,12 Some samples were genotyped in previous studies, including 6- to 8-week samples from 282 (92%) of the 306 women enrolled in HIVNET 012 (all available 6- to 8-week samples),17 and 7-day samples from 93 (30%) of the 306 women.19 At the time the latter study was performed, 7-day samples from the remaining women in the NVP arm of HIVNET 012 were reserved for other trial-related testing and were not available for genotyping. All of the remaining 7-day samples (samples from 150 additional women) were subsequently made available for genotyping and were analyzed in this extended study. The final 7-day sample set available for genotyping included samples from 243 (79%) of the 306 women who received NVP in HIVNET 012. The final data set used for analysis in this report included data from 140 of those women who had genotyping results obtained from both the 7 day and 6- to 8-week visits (paired data).
HIV-1 genotyping was performed with the ViroSeq HIV-1 Genotyping System (Celera Diagnostics, Alameda, CA). Genotypes were analyzed only if bidirectional sequence data were obtained at all positions of NVPR mutations. Sequences were examined for mutations associated with NVPR (A98G, L100I, K101E, K103N, V106A, V108I, V179D Y181C/I, Y188C/H/L, G190A/S, M230L), as well as accessory mutations (K101Q, V106I, P225H, Y318F) and mutations associated with NVP hypersusceptibility (P236L) (IAS-USA Drug Resistance Mutations Group 2002, Stanford HIV RT and Protease Sequence Database: http://hivdb.stanford.edu/cgi-bin/NNRTIResiNote.cgi).
HIV-1 pol region sequences generated with ViroSeq system were aligned using the Clustal V algorithm (MegAlign Program, DNASTAR, Madison, WI). HIV-1 subtyping was performed by phylogenetic analysis of same sequences using PHYLIP v.3.572, as previously described.17
Baseline viral load and baseline CD4 cell count were compared in different groups using the T-test (SAS version 8.2; SAS, Cary, NC). The change in the prevalence of NVPR mutations detected at 7 days vs. 6 to 8 weeks after single-dose NVP administration was compared in women with subtype A vs. D using the GEE (generalized estimating equation, SAS version 8.2). The GEE is a method of parameter estimation for correlated data that allows correlation of repeated observations made in the same subjects over time. The probability distribution was binomial (binary outcome variable) and the logit link function was used. An interaction between time and subtype was included to test whether NVPR mutations had different rates of fading in women with subtype A vs. D. Because there were only 2 time points in our study, the analysis should yield similar results by using different correlation matrices. The analysis employed an unstructured correlation matrix.28,29
GenBank Accession Numbers
GenBank accession numbers for samples collected 7 days or 6 to 8 weeks after NVP are listed the end of the paper.
Data Set Used for Analysis
In HIVNET 012, 306 women received single-dose NVP. This study included analysis of all available samples collected from women either 7 days or 6 to 8 weeks after NVP administration. This included 243 samples collected 7 days after NVP and 282 samples collected 6 to 8 weeks after NVP (see “Methods”). The mean of baseline viral load and the mean of baseline CD4 cell count were similar among the 243 women who had a 7-day sample available for analysis and the 63 women who did not have a sample (P = 0.272 for viral load, P = 0.676 for CD4 cell count). Genotyping was successful for 279 (99%) of the 6- to 8-week samples but for only 173 (71%) of the 7-day samples. The higher rate of amplification failure for the 7-day samples most likely reflected the lower viral loads in those samples. Sixty-one of the 70 samples that failed had viral loads <2000 copies/mL. The 70 women whose 7-day samples failed to amplify also had lower mean baseline viral loads and higher mean baseline CD4 cell counts than the 173 women for whom resistance results were obtained (P < 0.0001 for viral load, P < 0.0001 for CD4 cell count). Amplification failures were unlikely to reflect genetic diversity of the HIV-1 in these women, because samples from the same women collected at other trial visits (eg, pre-NVP or 6 to 8 weeks after NVP) were successfully analyzed. The HIV-1 subtype distribution among the 173 women whose 7-day samples were successfully genotyped was 51% subtype A, 37% subtype D, 2% subtype C, and 10% intersubtype recombinant HIV-1. There was no evidence of dual-subtype infection. That subtype distribution was not significantly different from the subtype distribution among the 70 women whose 7-day samples failed to amplify (66 of whom had subtyping results, P = 0.86, Mantel-Haenszel χ2) or among the 133 women without 7-day genotyping results (70 women whose 7-day samples failed to amplify plus 63 women with no 7-day sample, P = 0.54, Mantel-Haenszel χ2).
We analyzed data from the 140 women with either subtype A or D who had genotyping results obtained for both the 7-day and 6- to 8-week visits (paired data). This included 83 women with subtype A and 57 women with subtype D. For each sample, HIV-1 genotyping generated a sequence corresponding to protease amino acids 1-99 and RT amino acids 1-324. Phylogenetic reconstructions were performed using sequences from the 7-day and 6- to 8-week visits from those women. In each case, sequences from individual women from the 2 time points clustered together, indicating an absence of sample mix-ups or cross-contamination.
Rate of NVPR at 7 Days vs. 6-8 Weeks in Subtype A vs. D
We first compared the overall rate of NVPR (detection of any NVPR mutation) at 7 days vs. 6 to 8 weeks in women with subtypes A or D (paired samples). When the 140 women with these 2 subtypes were considered as a single group, the rate of NVPR was significantly higher at the 6- to 8-week visit (47/140 = 34%) than at the 7-day visit (31/140 = 22%) (P = 0.013, χ2; odds ratio [OR] = 1.92; 95% CI, 1.29, 2.85, significant at α = 0.05, Figure 1A dashed line). The continued accumulation of NVPR mutations after the 7-day visit was not surprising, given the long half-life of NVP (see above). We then compared results for women with subtype A vs. subtype D. This revealed that the rate of NVPR was similar in subtype A (20/83 = 24%) vs. D (11/57 = 19%) at the 7-day visit (P = 0.502) but was higher in subtype D (24/57 = 42%) than A (23/83 = 28%) at 6 to 8 weeks (P = 0.076). When the 7-day and 6- to 8-week data were compared, we found that the rate of accumulation of NVPR mutations between these visits was higher for subtype D than A (Fig. 1A, dashed line).
We then compared results from women with subtype A vs. subtype D (Fig. 1A, solid lines). This difference in the rate of accumulation in the 2 subtypes was analyzed using the GEE method. The odds of NVPR for subtype D were 0.753 times the odds for NVPR for subtype A at 7 days (slightly more resistance in subtype A at 7 days) but were 1.897 times higher for subtype D than A at 6 to 8 weeks (more resistance in subtype D at 6 to 8 weeks). The ratio of those 2 numbers (1.90/0.75 = 2.52) provides an OR for the difference in the rate of accumulation of NVPR in the 2 subtypes over time (OR = 2.52; 95% CI, 1.14, 5.59, P = 0.023). This confirms that the difference in the rate of accumulation of NVPR in the 2 subtypes is statistically significant. Similar results were obtained when baseline viral load and baseline CD4 cell counts were included as covariates in the analysis (P = 0.029). This indicates that the difference in the rate of accumulation in the subtypes was independent of baseline viral load and baseline CD4 cell count (ie, those factors were not confounders in the analysis30).
Rate of Detection of K103N at 7 Days vs. 6-8 Weeks in Subtype A vs. D
We next compared the rate of detection of the NVPR mutation, K103N, at 7 days vs. 6 to 8 weeks. When the 140 women with subtype A and D were considered as a single group, the overall rate of detection of K103N was higher at 6 to 8 weeks (41/140 = 29%) than at 7 days (18/140 = 13%) (P < 0.0001, χ2; OR = 2.93; CI 95%, 1.75, 4.89, significant at α = 0.05). This indicates that the K103N resistance mutation accumulated between the 2 visits in the group as a whole (Fig. 1B, dashed line). Furthermore, differences were observed when the rates of detection of K103N at the 2 visits were compared in women with subtype A vs. D (Fig. 1B, solid lines). The odds of detecting K103N in subtype D were 0.916 times those for subtype A at 7 days (slightly higher rate of K103N in subtype A at 7 days) but were 1.596 times higher for D than A at 6 to 8 weeks (higher rate of K103N in subtype D at 6 to 8 weeks). The ratio of those 2 numbers (1.60/0.92 = 1.74) provides an OR for the difference in the rates of detection of K103N in the 2 subtypes over time (OR = 1.74; 95% CI, 0.62, 4.87, P = 0.290). This analysis shows that K103N accumulated at a greater rate in women with subtype D between the 2 visits but that this trend was not statistically significant.
Rate of Detection of Y181C at 7 Days vs. 6-8 Weeks in Subtype A vs. D
We next compared the rate of detection of the NVPR mutation, Y181C, at 7 days vs. 6 to 8 weeks. When the 140 women with subtype A and D were considered as a single group, the overall rate of detection of Y181C was higher at 7 days (26/140 = 19%) than at 6 to 8 weeks (15/140 = 11%) (P = 0.015, χ2; OR = 0.51, 95% CI, 0.30, 0.87, significant at α = 0.05). This indicates that the Y181C mutation faded from detection between the 2 visits in the group as a whole (Fig. 1C, dashed line). In addition, differences were observed when the rates of detection of Y181C at the 2 visits were compared in women with subtype A vs. D (Fig. 1C, solid lines). Specifically, Y181C faded more quickly in subtype A than D. The odds of detecting Y181C were 1.08 times higher for D than A at 7 days and were 3.319 times higher for D than A at 6 to 8 weeks. The ratio of those 2 numbers (3.32/1.084 = 3.06) provides an OR for the difference in the rates of detection of Y181C in the 2 subtypes over time (OR = 3.06; 95% CI, 1.04, 9.0, P = 0.042). This analysis confirms that the rate of fading of Y181C is significantly faster in subtype A than D (P = 0.042).
Rate of Detection of G190A at 7 Days vs. 6-8 Weeks in Subtype A vs. D
A similar analysis was performed for the NVP resistance mutation G190A. That analysis suggested that G190A accumulated in subtype D between the 2 visits but not in subtype A (Fig. 1D). However, the number of G190A mutations detected in this subset of women was too small for meaningful statistical analysis. Other NVPR mutations (eg, V106A and Y188C) were noted in a small number of women.
Analysis of Potential Bias Introduced by Use of Paired Samples
The analysis described here was limited to women who had resistance results obtained from paired samples (collected 7 days and 6-8 weeks after NVP administration). To address whether limitation of the analysis to paired samples underestimated changes in NVPR rates between the 2 time points, we performed a similar statistical analysis including all samples with genotyping results (not just paired samples) and adjusted the analysis for baseline viral load and CD4 cell count in the GEE model. When the rates of accumulation of NVPR mutations in the 2 subtypes were compared, similar trends were observed (for resistance, OR = 3.07; 95% CI, 1.29, 7.32, P = 0.01; for K103N, OR = 2.09; 95% CI, 0.69, 6.37, P = 0.19; for Y181C, OR = 3.41; 95% CI, 1.23, 9.21, P = 0.02).
This study demonstrates that HIV-1 subtype can influence emergence and fading of specific NVPR mutations after single-dose NVP exposure. Different dynamics of selection and fading were observed for different NVPR mutations (eg, K103N, Y181C, G190A). This most likely reflects complex effects of each mutation on viral replication capacity in the presence and absence of NVP.
In this study, rapid fading of variants with Y181C was observed for women with subtype A, but not for women with subtype D. In subtype B viruses, the Y181C mutation confers a high level of phenotypic NVPR in vitro.31 This would favor rapid selection of Y181C-containing variants after NVP exposure, consistent with the predominance of the Y181C mutation in women as early as 1 to 2 weeks after single-dose NVP.19,32 In the absence of NVP, subtype B variants with Y181C have significantly reduced fitness compared with wild-type virus,33,34 which would favor rapid fading of the mutation after NVP exposure. The persistence of the Y181C in women with subtype D suggests that Y181C may have less of a negative impact on viral fitness in a subtype D background.
In this study, the K103N mutation continued to accumulate between 7 days and 6 to 8 weeks in both subtypes A and D; however, the rate of accumulation was higher for subtype D. The predominance of the K103N mutation in women 6 to 8 weeks after single-dose NVP (after NVP has been cleared) is consistent with in vitro studies that show that the K103N mutation confers a relatively small fitness cost in subtype B.33-35 Variants with the K103N mutation can persist for years in the absence of antiretroviral exposure in patients who are infected with resistant strains.36 Because samples were not available between these 2 visits (at a time when selection may have been maximal), it is not possible to infer whether greater accumulation of K103N in subtype A reflects faster selection of K103N-containing variants in subtype D while NVP was still present (ie, higher antiretroviral drug resistance in subtype D) or faster fading of K103N-containing variants in subtype A after NVP was cleared (ie, lower replication capacity of subtype A variants with K103N in the absence of the drug), or both.
This study suggests that NVPR may persist for longer periods after single-dose NVP in individuals with certain subtypes. Other studies using population-sequencing based methods for HIV genotyping have found different rates of NVPR months after NVP exposure in different cohorts. In HIVNET 012, NVPR mutations faded from detection in all evaluable Ugandan women by 12 to 24 months postpartum (including 3 with subtype A and 8 with subtype D).18 In HIVNET 023, NVPR mutations faded from detection in all but 1 of 33 Zimbabwean woman with subtype C by 24 weeks postpartum in HIVNET 023.32 In contrast, in South African cohorts, NVPR mutations were still detectable in many women with subtype C infection 6 to 12 months after NVP prophylaxis.25,37 Preliminary reports using more sensitive assays for detection of NVPR mutations reveal that NVPR mutations persist at low levels in many women for a year or more after NVP exposure.38-40 The clinical significance these findings is not known. A recent preliminary report from Thailand suggests that the virologic response to a nonnucleoside RT inhibitor-containing regimen may be reduced in women who had previously received a prophylactic regimen that included both single-dose NVP and a short course of zidovudine.41 Further studies are needed to determine whether single-dose NVP prophylaxis compromises efficacy of NNRTIs for prevention or treatment of HIV-1 infection, especially years after NVP exposure. Those studies are likely to be performed in resource-poor settings where non-subtype B is prevalent. This report suggests that HIV-1 subtype should be considered in the design and interpretation of those studies.
HIV-1 drug resistance can be avoided in most women in this setting by providing pregnant women with potent combination antiretroviral therapy. Such regimens are also more effective than single-dose NVP for pMTCT and have health benefits for the mother. However, in Uganda and other resource-limited countries, few individuals currently have access to antiretroviral treatment. Simple regimens for pMTCT, such as the HIVNET 012 regimen, are likely to be used. Despite the potential for emergence of NVPR with this regimen, the regimen offers hope for preventing HIV-1 infection in thousands of infants around the world. If future studies show that nonnucleoside reverse transcriptase inhibitor-based regimens are less effective in women who received single-dose NVP, and if antiretroviral drugs are available, those women could be offered treatment with other regimens.
The authors thank the HIVNET 012 team for providing the samples used in analysis. We acknowledge the assistance of Melissa Allen (protocol specialist, Family Health International) and thank Estelle Piwowar-Manning, Constance Ducar, and the laboratory staff in Uganda for assistance with sample processing.
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41. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med
GenBank accession numbers: Sequences from samples collected 7 days after NVP dosing:
AY428667-9, AY428671-3, AY428675, AY428677-83, AY428685-92, AY428695-710, AY428712-23, AY428725-32, AY428864, AY955692-772. Sequences from samples collected 6-8 weeks after NVP dosing:
AF388070-2, AF388075, AF388078, AF388081, AF388083, AF388085, AF388088, AF388092, AF388096-8, AF388101, AF388104-5, AF388108, AF388112-3, AF388115, AF388120, AF388125, AF388129-30, AF388132-3, AF388138-40, AF388145-6, AF388148, AF388152, AF388157, AF388159, AF388162, AF388164, AF388166, AY135367, AY388119, AY388121, AY423353, AY425349, AY425351, AY425354-7, AY435220-2, AY435225-32, AY435234, AY435237, AY435239, AY435243-8, AY435250-1, AY435256-7, AY435261-2, AY435264-5, AY435267, AY435269-70, AY435272, AY435274, AY435276, AY435279, AY435281, AY435290, AY435295, AY435297-8, AY435300-3, AY435306, AY435309-10, AY435312, AY435315, AY435317-22, AY435327-8, AY435330-2, AY435336, AY435340-1, AY435344-7, AY435350, AY435352, AY435354-6, AY435358-64, AY435366, AY435368, AY435371-2, AY435375, AY435378-9, AY435381-4, AY435386, AY435388.
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